Formation of substituted 6-hydroxy-5-oxo-5,6-dihydrobenzo[c][2,7] naphthyridine upon photochemical transformation of nifedipine

Article abstract of DOI:10.1023/B:RUCB.0000012367.57360.18

Long-term exposure of nifedipine to daylight in ethanol gives 2,2′-bis[3,5-bis(methoxycarbonyl)-2,6-dimethylpyridin-4-yl]azoxybenzene and 6-hydroxy-1-methoxycarbonyl-2,4-dimethyl-5-oxo-5,6-dihydrobenzo[c] [2,7]naphthyridine as the major products.

Full text of DOI:10.1023/B:RUCB.0000012367.57360.18

2440
Russian Chemical Bulletin, International Edition, Vol. 52, No. 11, pp. 2440—2443, November, 2003
Formation of substituted
6ꢀhydroxyꢀ5ꢀoxoꢀ5,6ꢀdihydrobenzo[c][2,7]naphthyridine
upon photochemical transformation of nifedipine
V. P. Krivopalov, V. F. Sedova, and O. P. Shkurkoꢀ
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
9 prosp. Akad. Lavrent´eva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383 2) 34 4752. Eꢀmail: oshk@nioch.nsc.ru
Longꢀterm exposure of nifedipine to daylight in ethanol gives 2,2´ꢀbis[3,5ꢀbis(methoxyꢀ
carbonyl)ꢀ2,6ꢀdimethylpyridinꢀ4ꢀyl]azoxybenzene and 6ꢀhydroxyꢀ1ꢀmethoxycarbonylꢀ
2,4ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydrobenzo[c][2,7]naphthyridine as the major products.
Key words: 4ꢀ(2ꢀnitrophenyl)ꢀ3,5ꢀdimethoxycarbonylꢀ2,6ꢀdimethylꢀ1,4ꢀdihydropyridine,
4ꢀ(2ꢀnitrosophenyl)ꢀ3,5ꢀdimethoxycarbonylꢀ2,6ꢀdimethylpyridine, 2,2´ꢀbis[3,5ꢀbis(methoxyꢀ
carbonyl)ꢀ2,6ꢀdimethylpyridinꢀ4ꢀyl]azoxybenzene, 6ꢀhydroxyꢀ1ꢀmethoxycarbonylꢀ2,4ꢀdiꢀ
methylꢀ5ꢀoxoꢀ5,6ꢀdihydrobenzo[c][2,7]naphthyridine, intramolecular cyclization, photochemꢀ
istry, nifedipine.
Nifedipine (dimethyl 2,6ꢀdimethylꢀ4ꢀ(2ꢀnitrophenyl)ꢀ
1,4ꢀdihydropyridineꢀ3,5ꢀdicarboxylate (1)) is widely used
in practical medicine to treat cardiovascular diseases. It
easily undergoes transformations when treated with oxiꢀ
dants or reducing agents1—4 and is also capable of intraꢀ
and intermolecular transformations induced by ultravioꢀ
let and visible light.5—7
tive 6 and then to amino derivative 7, and, finally, intraꢀ
molecular cyclization of 7 to give lactam (5) (Scheme 1).
However, another study13 calls in question the particiꢀ
pation of amino ester 7 in the formation of lactam 5, as
this amino ester is a stable compound and requires more
rigorous conditions for cyclization.3 Lactam 5 is formed
5
upon irradiation of nifedipine in the presence of TiCl3
A number of studies8—13 have been devoted to the
composition and structure of the products of photochemiꢀ
cal transformations of nifedipine and its pelleted forms. It
was found that the reaction may proceed to different exꢀ
tents depending on the conditions applied, thus giving
different sets of products. Thus, on exposure to daylight
or soft UV light, nifedipine (1) gives dimethyl 2,6ꢀdiꢀ
methylꢀ4ꢀ(2ꢀnitrosophenyl)pyridineꢀ3,5ꢀdicarboxylate
(2) as the major product of the primary phototransforꢀ
mation, while harder UV radiation results in the formaꢀ
tion of dimethyl 2,6ꢀdimethylꢀ4ꢀ(2ꢀnitrophenyl)pyridineꢀ
3,5ꢀdicarboxylate (3).8,9 For longer exposure time, the
process goes further giving rise to other compounds due
to subsequent transformations of the primary photoꢀ
transformation products. Japanese researchers12 studied
the composition of a complex mixture of compounds proꢀ
duced upon a 30ꢀday exposure of nifedipine and its
pelleted forms to daylight. In addition to nitroso comꢀ
pound 2 (30%) and azoxy derivative 4 (20%), they isoꢀ
lated trace amounts of nitro compound 3 and 1ꢀmethꢀ
oxycarbonylꢀ2,4ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydrobenꢀ
zo[c][2,7]naphthyridine (lactam 5). The pattern of transꢀ
formations they proposed assumes the formation of nitroso
derivative 2, its reduction first to hydroxylamino derivaꢀ
or on treatment of nitroso derivative 2 with a reducing
agent such as glutathione in the dark.13 On the basis of the
foregoing, it has been assumed13 that lactam 5 is formed
from Nꢀhydroxylactam 8 rather than from amino ester 7.
However, the researchers cited did not succeed in detectꢀ
ing the formation of Nꢀhydroxylactam 8 during the
phototransformation of nifedipine, although this product
is a wellꢀknown compound, first prepared5 by careful reꢀ
duction of nitro derivative 3 with zinc.
We succeeded in identifying the conditions of photoꢀ
decomposition of nifedipine to give Nꢀhydroxylactam 8.
It was found that this compound is formed, together with
azoxy derivative 4, under usual laboratory conditions when
a mixture of primary photodecomposition products of
nifedipine (1) is kept in the light for many months. Thus a
solution of nifedipine in MeOH was kept for 6 months
and a solution in EtOH, for 10 months. Both solutions
turned brightꢀgreen several hours after the preparation,
which indicated the formation of nitrosophenylpyridine 2.
Subsequently, the color gradually changed from green to
yellowꢀbrown and a finelyꢀcrystalline colorless precipiꢀ
tate gradually accumulated on the walls. The precipitate
formed in each case was isolated, while the major compoꢀ
nents of the supernatant were separated by preparative
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2307—2310, November, 2003.
1066ꢀ5285/03/5211ꢀ2440 $25.00 © 2003 Plenum Publishing Corporation

Photochemical transformation of nifedipine
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003 2441
Scheme 1
TLC on silica gel (Table 1). In both cases, this resulted in
Both crystalline precipitates isolated from the methaꢀ
nol and ethanol solutions were identical but differed in
properties from lactam 5, which was described in detail
previously.12 We determined the composition and the
structure of the compound obtained based on spectroꢀ
scopic data. Its IR spectrum contains intense bands at
1714 cm–1 due to the ester group and at 1646 cm–1 due to
the hydroxamic group and a broad band at 3100 cm–1 for
isolation of transꢀazoxy derivative 4 and nitroso derivative
1
2 containing (according to TLC and H NMR spectrosꢀ
copy) traces of nitro derivative 3 difficult to separate.
Table 1. Values of Rf (TLC) for compounds 1—4 and 8
Comꢀ
pound
Conditionsa
the HO group. No band at 1675 cm–1 characteristic of
I
II
12
lactam 5
is present. The most intense peak in the
mass spectrum of 5 has m/z 298, which corresponds to
the molecular ion of Nꢀhydroxylactam 8. The 1H and
13C NMR spectra also confirm structure 8, having one
ester group and two methyl groups in the pyridine fragꢀ
ment; the spectra also exhibit the appropriate set of other
signals. The signals were assigned based on the assignꢀ
ment of signals for the corresponding acid.14 The sample
of 8 that we isolated from the ethanol solution conꢀ
tained a slight amount (∼5%) of the ethyl ester of this acid
1
2
3 b
4
0.63
0.86
0.85
0.50
0.54
0.24
0.68
0.62
0.30
8
∼0
a I — SiO2 (Silufol UVꢀ254)/CH2Cl2—MeOBut—C6H14, 2 : 2 : 1.
II — Al2O3 (DC Alufolien E)/CH2Cl2—C6H14, 1 : 1.
b The sample of compound 3 was synthesized by a known proꢀ
cedure.2

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Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003
Krivopalov et al.
Table 2. Products of phototransformation of nifedipine
tor (+4 °C). The resulting lightꢀgray precipitate was separated,
washed with MeOH, and dried in vacuo to give 6ꢀhydroxyꢀ
1ꢀmethoxycarbonylꢀ2,4ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydrobenꢀ
zo[c][2,7]naphthyridine (8), yield 0.03 g (3%), m.p. 193—195 °C
(from 96% EtOH). The compound developed an intense brownꢀ
violet color with FeCl3 and was identical to the product obꢀ
tained by phototransformation of nifedipine in 96% EtOH.
After separation of the crystalline precipitate, the solution
was concentrated to dryness, the residue was dissolved in benꢀ
zene, and the solution was passed through a layer of Al2O3
(1 cm) and concentrated. The residue was separated by preparaꢀ
tive TLC on silica gel (Silica gel LL254 5—40 µm, ∼1.5 mm thick
layer, elution with CH2Cl2—MeOBut—C6H14, 6 : 1 : 1) with
detection in the UV light. Two main zones were collected,
namely, Rf 0.6—0.7 (green zone) and 0.4—0.5 (yellow zone);
they were eluted with CHCl3. The eluates were filtered and
concentrated in vacuo and each product was subjected once
again to chromatography.
Solvent
τ/days
Yield (%)
2
4
8
MeOH
EtOH
∼180
∼300
51
4
22
52
3
23
Note. τ is the exposure time.
(MS peak with m/z 312) formed as a result of transꢀ
esterification. As compared to other products of nifedipine
transformation, Nꢀhydroxylactam 8 has substantially difꢀ
ferent mobilities on SiO2 and Al2O3 (see Table 1), which
facilitates its identification.
Table 2 shows the yields of the isolated products of
nifedipine transformation in MeOH and EtOH for differꢀ
ent photoexposure times of solutions. For low degrees of
transformation, nitroso derivative 2 is the major product,
while Nꢀhydroxylactam 8 is present in a small amount.
The ratio of the products changes for longer expoꢀ
sure times. The formation of azoxy compound 4 and
Nꢀhydroxylactam 8 indicates participation of two interꢀ
mediates in the transformations, namely, nitroso derivaꢀ
tive 2 and hydroxylamino derivative 6. The latter may be
produced from nitroso derivative 2 with participation of
other components of the mixture in conjugated redox
processes, including photochemical reactions.15
Thus, we showed that upon long exposure of an ethaꢀ
nol solution of nifedipine 1 to the light, 6ꢀhydroxyꢀ
1ꢀmethoxycarbonylꢀ2,4ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydroꢀ
benzo[c][2,7]naphthyridine (8) is formed as one of
the two major products. Recently, a similar derivative,
6ꢀhydroxyꢀ2,4ꢀdimethylꢀ5ꢀoxoꢀ5,6ꢀdihydrobenꢀ
zo[c][2,7]naphthyridine, was prepared by UV irradiation
of 3ꢀmethoxycarbonylꢀ2,6ꢀdimethylꢀ4ꢀ(2ꢀnitrophenyl)ꢀ
1,4ꢀdihydropyridine.16
The upper zone produced 0.5 g (51%) of a green crystalline
product, which was 2,6ꢀdimethylꢀ3,5ꢀbis(methoxycarbonyl)ꢀ4ꢀ
(2ꢀnitrosophenyl)pyridine (2), m.p. 85—90 °C (Ref. 5: m.p.
93 °C). 1H NMR (400 МHz, CCl4), δ: 2.60 (s, 6 H, Me); 3.30
3
4
(s, 6 H, OMe); 6.37 (dd, 1 H, H(6´), J5´,6´ = 8.0 Hz, J4´,6´
=
1.2 Hz); 7.34 (ddd, 1 H, H(5´), 3J5´,6´ = 8.0 Hz, 3J4´,5´ = 7.6 Hz,
4J3´,5´ = 1.2 Hz); 7.45 (dd, 1 H, H(3´), 3J3´,4´ = 7.6 Hz, 4J3´,5´
=
=
3
3
1.2 Hz); 7.63 (td, 1 H, H(4´), J3´,4´ = J4´,5´ = 7.6 Hz, 4J4´,6´
1.2 Hz). The 1H NMR and mass spectra also exhibited lowꢀ
intense peaks coinciding with those in the spectra of an authenꢀ
tic sample of nitro compound 3 (cf. Refs. 2, 12). MS, m/z:
328 (19) [M]+, 298 (34) [M – NO]+, 269 (100) [M – COOMe]+.
Highꢀresolution mass spectrum, m/z: 328.1063. C17H16N2O5.
Calculated: 328.1059.
The lower zone produced 0.21 g (22%) of transꢀ2,2´ꢀ
bis[2,6ꢀdimethylꢀ3,5ꢀbis(methoxycarbonyl)pyridinꢀ4ꢀyl]azoxyꢀ
benzene (4), m.p. 162—165 °C (from a benzene—hexane mixꢀ
1
ture) (Ref. 12: m.p. 163—165 °C). H NMR (400 МHz, CCl4),
δ: 2.45 and 2.49 (both s, each 6 H, Me); 3.25 and 3.26 (both s,
each 6 H, OMe); 7.00—7.04 (m, 2 H, Ar); 7.19 and 7.31 (both dt,
each 1 H, Ar, 3J = 8.5 Hz, 4J = 1.5 Hz); 7.40—7.42, 7.80—7.86
(both m, each 2 H, Ar). 13C NMR (100 МHz, CCl4), δ: 20.84
(Me), 21.11 (Me), 49.32 (OMe), 119.56, 121.95, 122.60, 124.39,
124.86, 125.57, 126.32, 126.38, 127.47, 127.68, 129.69, 131.81,
139.03, 142.41, 142.85, 144.83, 153.41, 154.13, 164.51 (C=O),
164.86 (C=O). MS, m/z: 641 [М + H]+, 581 [М+ – COOMe],
314 [М+ – C17H16N3O4], 298 [М+ – C17H16N3O5].
Experimental
IR spectra of the compounds were recorded on a Bruker
Phototransformation of nifedipine in ethanol. A solution of
nifedipine (1) (0.25 g, 0.72 mmol) in 10 mL of 96% ethanol was
kept in a closed glass flask for 10 months under the conditions
described above. The paleꢀyellowꢀgray precipitate was separated,
washed with 0.1 mL of 96% EtOH, and dissolved in CHCl3. The
solution was passed through a silica gel layer (1.5 cm) and eluted
with CHCl3. The eluates were concentrated in vacuo and the
colorless crystalline precipitate was recrystallized from 96% ethaꢀ
nol to give 6ꢀhydroxyꢀ1ꢀmethoxycarbonylꢀ2,4ꢀdimethylꢀ5ꢀoxoꢀ
5,6ꢀdihydrobenzo[c][2,7]naphthyridine (8), yield 0.05 g (23%),
m.p. 193—195 °C. The product was identical to the compound
(m.p. 194—196 °C) prepared by the reduction of dimethyl
2,6ꢀdimethylꢀ4ꢀ(2ꢀnitrophenyl)pyridineꢀ3,5ꢀdicarboxylate with
zinc (3) according to a procedure described previously5 (Ref. 5:
m.p. 210 °C). IR, ν/cm –1: 1252 (ester C—O), 1550, 1588,
1606 (conjug. C=C), 1646 (amide C=O), 1714 (ester C=O),
1
Vector 22 spectrophotometer for KBr pellets. H and 13C NMR
spectra were recorded on Bruker ACꢀ200 and Bruker AMꢀ400
spectrometers. Mass spectra were obtained on a Finnigan
MATꢀ8200 spectrometer (EI, 70 eV). The separation of comꢀ
pounds was monitored by TLC on Silufol UVꢀ254 plates
(Chemapol, Czechia) and DC Alufolien E plates (Merck, Gerꢀ
many); the spots were visualized in the UV light and compared
with authentic samples of compounds 1—4. All operations were
carried out in air.
Phototransformation of nifedipine in methanol. A solution of
nifedipine (1) (1.04 g, 3.0 mmol) in 30 mL of MeOH was kept in
a closed glass flask at room temperature (∼20 °C) under usual
room light (a combination of the natural daylight and artificial
light from a luminescent lamp). After 6 months, the yellowꢀ
brown solution was concentrated by half and left in a refrigeraꢀ

Photochemical transformation of nifedipine
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 11, November, 2003 2443
2820—3000 (C—H), 3100 (OH). MS, m/z: 298 (100) [М]+, 281
(81) [М – OH]+, 267 (21) [М – OMe]+. Highꢀresolution mass
spectrum, m/z: 298.0952. C16H14N2O4. Calculated: 298.0953.
1H NMR (200 МHz, CDCl3), δ: 2.66 (s, 3 H, C(4)CH3); 3.17
(s, 3 H, C(2)CH3); 3.99 (s, 3 H, OMe); 7.26 (ddd, 1 H, H(9),
4. N. Iqbal, C. R. Triggle, and E. E. Knaus, Drug Dev. Res.,
1997, 42, 120.
5. K. Görlitzer and D. Buss, Arch. Pharm. (Weinheim, Ger.),
1985, 318, 97.
6. K. Görlitzer and D. Buss, Arch. Pharm. (Weinheim, Ger.),
1985, 318, 106.
7. L. Born, S. Goldmann, C. Wünsche, K. Görlitzer, and
D. Buss, Arch. Pharm. (Weinheim, Ger.), 1988, 321, 855.
8. S. Ebel, H. Shütz, and A. Hornitschek, Arzneim.ꢀ
Forsch./Drug Res., 1978, 28, 2188.
9. R. Testa, E. Dolfini, C. Reschiotto, C. Secchi, and P. A.
Biondi, Farmaco, Ed. Prat., 1979, 34, 463; Chem. Abstr.,
1980, 92, 51589.
10. K. Akimoto, K. Kurosaka, H. Nakagawa, and I. Sugimoto,
Chem. Pharm. Bull., 1988, 36, 1483.
11. Y. Matsuda, R. Teraoka, and I. Sugimoto, Int. J. Pharm.,
1989, 54, 211; Chem. Abstr., 1990, 112, 11831.
12. N. Hayase, Yu.ꢀI. Itagaki, S. Ogawa, Sh. Akutsu,
Sh.ꢀI. Inagaki and Y. Abiko, J. Pharm. Sci., 1994, 83, 532.
13. H. de Vries and G. M. J. Beijersbergen van Henegouwen,
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3
4
3J9,10 = 8.4 Hz, J8,9 = 7.1 Hz, J7,9 = 1.4 Hz); 7.66 (ddd, 1 H,
3
3
4
H(8), J7,8 = 8.4 Hz, J8,9 = 7.1 Hz, J8,10 = 1.0 Hz); 7.81 (dd,
1 H, H(7), 3J7,8 = 8.4 Hz, 4J7,9 = 1.4 Hz); 7.92 (dd, 1 H, H(10),
3J9,10 = 8.4 Hz, J8,10 = 1.0 Hz); 10.85 (s, 1 H, OH). 13C NMR
4
(50 МHz, CDCl3), δ: 23.0 (Me), 26.9 (Me), 52.9 (OMe), 113.2
(C(7)), 114.6 (C(10a)), 115.1 (C(4a)), 121.4 (C(1)), 122.9
(C(9)), 125.7 (C(10)), 132.1 (C(8)), 134.7 (C(10b)), 137.1
(C(6a)), 155.6 (C(2)), 156.6 (C(4)), 162.8 (C(N)=O), 170.5
(C(O)=O).
After separation of the crystalline precipitate, the solution
was concentrated, the residue was dissolved in benzene, and the
solution was passed through an Al2O3 layer. The resulting mixꢀ
ture was separated by TLC as described above. From the upper
zone, 0.01 g (4%) of nitrosophenyl derivative 2 was isolated, and
0.12 g (52%) of azoxy derivative 4 was isolated from the
lower zone.
14. E. Gössnitzer, K. Görlitzer, and H. J. Baltrusch, Magn. Res.
Chem., 2002, 40, 467.
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Received April 3, 2003;
in revised form July 1, 2003